1. Biology of Cancer and Tumor Spread
Chapter 9

2. First Medial Description :Egyptian Text@ 2500BC-Imhotep

3. Mastectomy: Johannes Scultetus (1595-1645)-fire, acid, leather binding

4. Tumor – 1922
“it is tissue overgrowth that is independent of the laws governing the remainder of the body”
“neoplastic overgrowth serves no useful purpose to the organism”

5. Cancer
Modern: “uncontrolled clonal proliferation of cells that can arise from virtually any cell type in the body”
Derived from the Greek word for crab karkinoma – Hippocrates (460 – 370 BC)
Malignant tumors
Tumor
Also referred to as a neoplasm – new growth

6. Clonal Proliferation of a Single Cell “Storm Troopers: Star Wars”

7. Benign vs. Malignant Tumors
Grow slowly
Grow rapidly
Well-defined capsule
Not encapsulated
Not invasive
Invasive
Well differentiated
Poorly differentiated
Low mitotic index
High mitotic index
Do not metastasize
Can spread distantly (metastasis)

8. Classification & Nomenclature
Benign
Named according to the tissue from which they arise, and includes the suffix - “oma”
Lipoma
Glioma
Leiomyoma
Chondroma

9. Classification & Nomenclature
Malignant tumors
Named according to the cell type from which they arise
Epithelial tissue – carcinoma
Ductal or glandular epithelium – adenocarcinoma
Example: mammary adenocarcinoma
Connective tissue – sarcoma
Example: rhabdomyosarcoma
Lymphatics – lymphomas
Blood forming cells – leukemia

10. Classification & Nomenclature Carcinoma in situ (CIS)
Preinvasive epithelial malignant tumors of glandular or
squamous cell origin that have not broken through the basement membrane or invaded the surround stroma
Cervix, skin, oral cavity, esophagus and bronchus (epithelium)
Stomach, endometrium, breast, large bowel (glandular)

13. Stages of Cancer Spread
“important component to diagnosis and treatment”
Physical findings
Laboratory tests – histological/biochemical/genetic
Imaging studies

14. Breast Cancer

16. Cancer Cells
Transformation
Autonomy
Cancer cells: independent from normal cellular controls
Anaplasia
Loss of differentiation (specialization and organization)
“without form” - pleomorphic

18. Cancer and Stem Cells Cell divisions create new stem cells
Stem cells self-renew
Cell divisions create new stem cells
Stem cells are pluripotent
Ability to differentiate into multiple different cell types

19. Stem Cell

21. Cancer…a genetic disease
DNA RNA Proteins(workhorse of the cell)
“normal regulated growth”
DNA** RNA** Proteins**
1. Plasma membrane **
2. Intracellular enzyme system**
3. Hormones/Growth factors**
“unregulated growth…colonal proliferation
** multiple mutations- how many?

22. Cancer…a genetic disease
DNA** RNA** Proteins**(antigen)
Example:
EarlyCDT-Lung (Oncoimmune)-blood test
6 cancer associated antigens (p53, +5)
Autoantibodies…against abnormal proteins**
Medscape Medical News Sept 20,2010

24. Tumor Markers (DNA…RNA…Proteins)
Tumor cell markers (biologic markers) are substances produced by cancer cells or that are found on tumor plasma cell membranes, in the blood, CSF, or urine
Hormones
Enzymes
Genes
Antigens
Antibodies

25. Tumor Markers Table 9-2
Used
Screen and identify individuals at high risk for cancer(CA-125, PSA, CEA, Bense Jones protein)
Diagnose specific types of tumors
Observe clinical course of cancer

26. Types of Genetic Lesions in Cancer
Point mutation
Subtle alterations (insertions, deletions, translocation)
Chromosome changes (aneuploidy and loss of heterozygosity)
Amplification
Gene silencing
Exogenous sequences (tumor viruses)

27. Genetic Basis of Cancer
Cancer-causing mutations
Disease of aging (more mutation over time)
Clonal proliferation or expansion
Mutation leads to a Darwinian
Survival advantage
(↑ growth or ↓ apoptosis)
Multiple mutations are required before cancer can develop (how many?)

29. Oncogenes and Tumor-Suppressor Genes
Proto-oncogene/Oncogenes
Mutant genes that in their non-mutant state direct protein synthesis and cellular growth (acceleration- pedal to the metal)
Tumor-suppressor genes
Encoded proteins that in their normal state negatively regulate proliferation
Also referred to as antioncogenes (put the brakes on)

30. Types of Mutated Gene:” 7 mechanisms”
Secretion of growth factors (autocrine stimulation)
Increased growth factor receptors (HER2/neu)
Signal from cell-surface receptors is mutated to the “on” position
Mutation in the ras intracellular signaling protein – (cell growth without growth factors) : “kinase”
“all lead to increase growth”

31. Types of Mutated Genes

32. Types of Mutated Genes:”7 mechanisms”
Inactivation of Rb tumor suppressor(tumor suppression) inherited
Activation of protein kinase* that drive the cell cycle (oncogene)
Mutation in the p53 gene (# apoptosis)-tumor suppression gene 17p13.1
*-PO4: activates and amplifies enzymatic processes over and over…

33. Types of Mutated Genes:Bowel Cancer

34. Question: How many mutations does it take to cause cancer?
“Cancer Genome Atlas”-breast cancer 127 mutations
Driver mutations: (average=13)-directly cause growth and survival of the cancer; hit oncogenes/tumor suppression genes; limited number exist
Bystander/passenger mutations: accidental copying of DNA; no impact on the biology of cancer

35. Driver Mutations
“Core metabolic pathway leads to dysregulation of any tumor”
One or more proto-oncogene/tumor suppression gene may skip mutation, but others mutations activate the core pathway
CANCER

36. Angiogenesis (core pathway)
Growth of new blood vessels
Advanced cancers can secrete angiogenic factors (VEGF)

39. Telomeres and Immortality: core
Body cells are not immortal and can only divide a limited number of times (double about 50 times - Hayflick Limit: 1961)
Telomeres are protective cap on each chromosome and are held in place by telomerase (germ cells & stem cells) enzyme
Telomeres become smaller and smaller with each cell division- “somatic cells” – quit dividing/die
Telomerase enzyme: rebuilds telomeres
Nobel Prize 2009:Blackburn, Greider, Szostak

40. Telomeres and Immortality

41. Mutations of Normal Genes → Cancer Genes
Point mutation (most common)
Change of one or a few nucleotide base pairs
ras gene (pancreatic, colon)
Chromosome translocation
A piece on one chromosome is transferred to another
t(8;14) Burkitt Lymphoma
t(9;22) chronic myeloid leukemia (Philadelphia chromosome – 1960)

42. Mutations of Normal Genes → Cancer Genes
Chromosome amplification
Duplication of a small piece of chromosome (DNA) over and over
Result in ↑ expression of an oncogene
N-myc 25% amplification

43. Mutation of Normal Genes

44. Oncogenes and Tumor-Suppressor Genes Oncogenes
Mutant genes that in their non-mutant state direct protein synthesis and cellular growth (jammed acceleration)
Tumor-suppressor genes
Encoded proteins that in their normal state negatively regulate proliferation
Also referred to as antioncogenes (put the brakes on)

45. Mutations of Normal Genes →Cancer Genes
Tumor-suppression genes(“inherited”)
Unregulated cellular growth (put on the brakes) Rb gene (inactivated) → retinoblastoma, lung, breast, bone
Two hits or mutations to inactivate the genes(Rb)
Childhood retinoblastomas: 2 forms-inherited(2-6 mo.)/sporadic(2-4 yrs)
De Gouvea(1872)-Brazilian Ophthmol. :young boy & his 2 daughters= cancer can be inherited

46. Mutations of Normal Genes → Cancer Genes
Loss of heterozygosity
Loss of a chromosome region in one chromosome
Unmasks mutation in the other locus of a tumor suppression gene

47. Mutation of Normal Genes: Tumor Suppression Genes

48. Mutations of Normal Genes → Cancer Genes
Gene silencing
No mutation or change in DNA sequence
Whole regions of chromosomes are shut off while the same regions in other cells remain active
Shuts off critical tumor suppression genes

49. Mutations of Normal Genes → Cancer Genes
Caretaker genes(“inherited”)
Encode for proteins that are involved in repairing damaged DNA (UV or ionizing radiation, chemicals and drugs)
Loss lead to increase mutation rates
Chromosome instability
Increase in malignant cells
Results in chromosome loss, loss of heterozygosity and chromosome amplification
Loss of tumor suppression genes with overexpression of oncogenes

50. Genetics and Cancer-Prone Families
Somatic cells – most cancers
Exposure to mutagen
Defect in DNA repair
Not inherited
Germ line cells (sperms and eggs)
Vertical transmission of cancer causing genes
Tumor suppression and caretaker genes
One mutant allele (mom or dad), loss of heterozygosity in some cells → tumors

51. Viruses and Cancer Implicated Hepatitis B & C viruses*
Epstein-Barr Virus (EBV)
Kaposi’s Sarcoma Herpes Virus (KSHV)
Human Papillomavirus (HPV)*
Human T cell Leukemia – Lymphoma Virus (HTLV)
*80% virus-linked cancers

52. Bacterial Causes of Cancer
Helicobacter pylori
Chronic infections associated with:
Peptic ulcer disease
Stomach carcinoma
Mucosa-associated lymphoid tissue lymphoma

53. Immunity and Cancer Viral-induced cancers Immune defect –
Surveillance – “nonself”
Viral-induced cancers
Immune defect –
HIV /immunosuppressants
↑ viral cancers
Organ transplant – immunosuppression – little or no ↑ in prevalent cancers
So → ?

54. Immunity and Cancer Chronic inflammation – “complex” Diseases
Cytokine release form inflammatory cells – may promote growth
Free radicals
Mutation promotion
↓ response to DNA damage
Diseases
Ulcerative colitis – 30x ↑
Liver – HBV/HBC - ↑ risk
Lung cancer – chronic asthma ↑66%

56. Cancer Progression and Metastasis
Metastasis – “a defining characteristic of cancer”
Localized may be cured(“in situ”)
Breast : 5 year survival > 90% - local
5 year survival < 3% - metastatic
Pattern of spread
Vascular, lymphatic and natural tissue planes
Selectivity
Breast to bone, not kidney or spleen
Lymphomas to spleen, not bone

57. “appropriate cancer “seed” and a permissive “soil”
Distant Metastasis
Cancer cells must detach(invade) and migrate from its primary location
Survive passage through the body
Attach, invade and multiply while stimulating angiogenesis
Thus:
#1. Vast majority of cancer cells do not have the
ability to form metastasis
“appropriate cancer “seed” and a permissive “soil”

58. Therapy for Cancer Surgery (1800-1900s)
Halsted Radical vs simple mastectomy vs local excision + radiation
Chemotherapy 3 to 7 drugs (ALL)
Bone marrow transplant-maximum chemotherapy
Radiation to tumors(Hodgkin’s lymphoma)
Targeted: mutated gene’s protein
Breast cancer +Her-2 membrane receptor: antibody:Herceptin
CML: kinase signal inhibitor: Gleevec

59. Why do the cancer cells become resistant to chemo/targeted therapy?
A few stem cells of the cancer mutate and produce a new protein product that specific chemo/targeted therapy can no longer inhibit and kill.
A new generation of resistant cancer cells evolves

60. Clinical Manifestations of Cancer Pain
Little or no pain is associated with early stages of malignancy
Influenced by fear, anxiety, sleep loss, fatigue and overall physical deterioration
Mechanism
Pressure, obstruction, invasion of sensitive structures, stretching of visceral surfaces, tissue destruction and inflammation
Priorities of treatment
Control – rapid and complete (patient)
Prevention – of recurrence

61. Clinical Manifestations of Cancer Fatigue
Tiredness, weakness, lack of energy, exhaustion, lethargy, inability to concentrate, depression, sleepiness, boredom, lack of motivation and ↓ mental status
Most frequently reported symptom – cancer/treatment
Mechanism – poorly understood

62. Clinical Manifestations of Cancer Cachexia
Most severe form of malnutrition
Present in 80% of cancer patients at death
Includes
Anorexia, early satiety, weight loss, anemia asthenia, taste alterations and altered protein, lipid and carbohydrate metabolism
Mechanism – multifactoral
Hormones (leptin)
Neuropeptides
Pro-inflammatory cytokines

63. Cachexia

64. Clinical Manifestations of Cancer
Anemia
Decreased amount of hemoglobin in the blood
Mechanisms
Chronic bleeding resulting in Fe deficiency, severe malnutrition, medial therapies or malignancy in blood forming organs
Suppression of erythropoietin on the bone marrow
rHuEPO

65. Clinical Manifestations of Cancer Leukopenia and thrombocytopenia
Direct tumor invasion to the bone marrow
Chemotherapy toxic to bone marrow
Infection
Risk increases when the absolute neutrophil and lymphocyte counts fall
ANC = WBC x (% neurophils + % bands), if < protective → isolation)
[Table 10-3 Review]

66. Clinical Manifestations of Cancer Paraneoplastic syndromes
Symptom complex unexplained by local or distant spread of the tumor or by the effects of hormones released by the tissues from which the tumor arose
10% of individuals
Earliest symptoms of an unknown cause
May represent serious and life threatening problems
May mimic cancer progression and interfere with appropriate treatment.
[Table 10-4] Review

67. Side Effects of Cancer Treatment
“targeting the most rapidly growing cells”
Gastrointestinal tract
Oral ulcers, malabsorption and diarrhea
Nausea and vomiting → antiemetic therapy
Supplemental nutrition (enteral or parenteral)
Bone marrow
Anemia – ↓RBC with fatigue
Platelets – bleeding
White blood cells – infection (ANC)